IBAT inhibitors for the treatment of liver diseases

ABSTRACT

The present invention regards specific IBAT inhibitors useful in the prophylaxis and/or treatment of a liver disease. It also relates to compositions comprising these IBAT inhibitors, a method for treatment of the disorders and a kit comprising the substances or the compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/069,199, filed Mar. 14, 2016, which is a continuation of U.S. patentapplication Ser. No. 13/881,447, filed May 17, 2013, which is a NationalStage application under 35 U.S.C. § 371 of International Application No.PCT/SE2011/051335, filed Nov. 8, 2011, which claims the benefit of U.S.Patent Application No. 61/410,957, filed Nov. 8, 2010, and SwedishPatent Application No. 1051165-7, filed Nov. 8, 2010, all of which areincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Ileal bile acid transporter (IBAT) is the main mechanism forre-absorption of bile acids from the GI tract. Partial or full blockadeof that mechanism will result in lower concentration of bile acids inthe small bowel wall, portal vein, liver parenchyma, intrahepaticbiliary tree, extrahepatic biliary tree, including gall bladder.

Diseases which may benefit from partial or full blockade of the IBATmechanism may be those either having as a primary pathophysiologicaldefect, causing or having symptoms of too high concentration of bileacids in serum and in the above organs. WO 2008/058630 describes theeffect of certain ileal bile acid transport (IBAT) in the treatment ofliver disease related to fat disorders.

SUMMARY OF THE INVENTION

The present invention regards specific IBAT inhibitors in theprophylaxis and/or treatment of a liver disease.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to IBAT inhibitory compounds of formula (I):

wherein:

-   -   M is CH₂, NH    -   One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the        other is selected from C₁₋₆alkyl;    -   R^(x) and R^(y) are independently selected from hydrogen,        hydroxy, amino, mercapto, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2    -   R^(z) is selected from halo, nitro, cyano, hydroxy, amino,        carboxy, carbamoyl, mercapto, sulphamoyl, C₂₋₆alkenyl,        C₂₋₆alkynyl C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl and N,N—(C₁₋₆alkyl)₂sulphamoyl;    -   v is 0-5;    -   one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB) or (IC):

wherein:

-   -   Y is N(R^(n))—, —N(R^(n))C(O)—,        —N(R^(n))C(O)(CR^(s)R^(t))_(v)N(R^(n))C(O)—, —O—, and —S(O)a-;        wherein a is 0-2, v is 1-2, R^(s) and R^(t) are independently        selected from hydrogen or C₁₋₄alkyl optionally substituted by        R²⁶ and R^(n) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; and when q is 0, R¹⁴ may additionally beselected from hydroxy wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1-3; wherein the values of R¹³ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different;

m is 0-2; wherein the values of R¹⁰ may be the same or different;

n is 1-3; wherein the values of R⁷ may be the same or different;

Ring B is a nitrogen linked heterocyclyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; and wherein if said nitrogen linkedheterocyclyl contains an —NH— moiety, that nitrogen may be optionallysubstituted by a group selected from R²⁵;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄ alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁴ and R²⁶ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, benzyloxycarbonylamino, sulpho, sulphino, amidino,phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²⁴ and R²⁶ may be independentlyoptionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

R²³ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(g))(OR^(h)),—P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) whereinR^(g) and R^(h) are independently selected from C₁₋₆alkyl;

R²⁵ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof for use in the prophylaxis or treatment of a liverdisease.

Compounds as used in accordance with the invention improve liver tests(serum amino transferases) and liver histology and significantly reducehydroxyproline content and the number of infiltrating neutrophils andproliferating hepatocytes and cholangiocytes.

In the literature IBAT inhibitors are often referred to by differentnames. It is to be understood that where IBAT inhibitors are referred toherein, this term also encompasses compounds known in the literature as:i) ileal apical sodium co-dependent bile acid transporter (ASBT)inhibitors; ii) bile acid transporter (BAT) inhibitors; iii) ilealsodium/bile acid cotransporter system inhibitors; iv) apical sodium-bileacid cotransporter inhibitors; v) ileal sodium-dependent bile acidtransport inhibitors; vi) bile acid reabsorption (BARI's) inhibitors;and vii) sodium bile acid transporter (SBAT) inhibitors; where they actby inhibition of IBAT.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes C₁₋₄alkyl, C₁₋₃ alkyl, propyl, isopropyland t-butyl. However, references to individual alkyl groups such as‘propyl’ are specific for the straight chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched chain version only. A similar conventionapplies to other radicals, for example “phenylC₁₋₆alkyl” would includephenylC₁₋₄alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term“halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

“Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing3-12 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Preferably “heteroaryl” refers to a totally unsaturated,monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. In another aspect of the invention, “heteroaryl” refers to atotally unsaturated, monocyclic ring containing 5 or 6 atoms or abicyclic ring containing 8, 9 or 10 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked. Examples and suitable values ofthe term “heteroaryl” are thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl,pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably the term“heteroaryl” refers to thienyl or indolyl.

“Aryl” is a totally unsaturated, mono or bicyclic carbon ring thatcontains 3-12 atoms. Preferably “aryl” is a monocyclic ring containing 5or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable valuesfor “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)— or a ring sulphur atom may beoptionally oxidised to form the S-oxides. Preferably a “heterocyclyl” isa saturated, partially saturated or unsaturated, mono or bicyclic ringcontaining 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂-group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form S-oxide(s). Examples and suitable values of the term“heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo [2.2.1] heptyl,4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl,indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Preferably “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or1-oxoindanyl.

An example of “C₁₋₆alkanoyloxy” and “C₁₋₄alkanoyloxy” is acetoxy.Examples of “C₁₋₆alkoxycarbonyl” and “C₁₋₄alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₆alkoxy” and “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy.Examples of “C₁₋₆alkanoylamino” and “C₁₋₄alkanoylamino” includeformamido, acetamido and propionylamino. Examples of “C₁₋₆alkylS(O)_(a)wherein a is 0 to 2” and “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” includemethylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl andethylsulphonyl. Examples of “C₁₋₆alkanoyl” and “C₁₋₄alkanoyl” includeC₁₋₃alkanoyl, propionyl and acetyl. Examples of “N—(C₁₋₆alkyl)amino” and“N—(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” and “N,N—(C₁₋₄alkyl)₂amino” includedi-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₆alkynyl” and “C₂₋₄alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” and“N—(C₁₋₄alkyl)sulphamoyl” are N—(C₁₋₃alkyl)sulphamoyl,N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)₂sulphamoyl” and “N-4alkyl)₂sulphamoyl” areN,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)carbamoyl” and “N—(C₁₋₄alkyl)carbamoyl” aremethylaminocarbonyl and ethylaminocarbonyl. Examples of“N,N—(C₁₋₆alkyl)₂carbamoyl” and “N,N—(C₁₋₄alkyl)₂-carbamoyl” aredimethylaminocarbonyl and methylethylaminocarbonyl. Examples of“C₁₋₆alkoxycarbonylamino” are ethoxycarbonylamino andt-butoxycarbonylamino. Examples of “N′—(C₁₋₆alkyl)ureido” areN′-methylureido and N′-ethylureido. Examples of “N—(C₁₋₆alkyl)ureido areN-methylureido and N-ethylureido. Examples of “N′,N′—(C₁₋₆alkyl)₂ureidoare N′,N′-dimethylureido and N′-methyl-N′-ethylureido. Examples of“N′—(C₁₋₆alkyl)-N—(C₁₋₆alkyl)ureido are N′-methyl-N-methylureido andN′-propyl-N-methylureido. Examples of“N′,N′—(C₁₋₆alkyl)₂-N—(C₁₋₆alkyl)ureido areN′,N′-dimethyl-N-methylureido and N′-methyl-N′-ethyl-N-propylureido.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid.

In addition a suitable pharmaceutically acceptable salt of a compound ofthe invention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl) amine.

Compounds of formula (I) may be administered in the form of a pro-drugwhich is broken down in the human or animal body to give a compound ofthe formula (I).

Examples of pro-drugs include in vivo hydrolysable esters and in vivohydrolysable amides of a compound of the formula (I).

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C_(3-s)cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxy-carbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of theformula (I) containing a carboxy group is, for example, a N—C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N, N-diethyl amide.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess IBAT inhibitory activity.

Preferred values of R¹, R², R³, R⁴, R⁵ and R⁶ are as follows. Suchvalues may be used where appropriate with any of the definitions, claimsor embodiments defined hereinbefore or hereinafter.

Preferably R¹ and R² are independently selected from C₁₋₄alkyl.

More preferably R¹ and R² are independently selected from ethyl orbutyl.

More preferably R¹ and R² are independently selected from ethyl, propylor butyl.

In one aspect of the invention particularly R¹ and R² are both butyl.

In a further aspect of the invention particularly R¹ and R² are bothpropyl.

In another aspect of the invention particularly one of R¹ and R² isethyl and the other is butyl.

Preferably R^(x) and R^(Y) are independently selected from hydrogen orC₁₋₆alkyl.

More preferably R^(x) and R^(Y) are both hydrogen.

Preferably R^(Z) is selected from halo, amino, C₁₋₆alkyl,C₁₋₆alkoxycarbonylamino or N′—(C₁₋₆alkyl)ureido.

More preferably R^(Z) is selected from chloro, amino, t-butyl,t-butoxycarbonylamino or W-(t-butyl)ureido.

Preferably v is 0 or 1.

In one aspect of the invention, more preferably v is 0.

In one aspect of the invention, more preferably v is 1.

In one aspect of the invention preferably R⁴ is a group of formula (IA)(as depicted above).

In another aspect of the invention preferably R⁵ is a group of formula(IA) (as depicted above).

Preferably R³ and R⁶ are hydrogen.

Preferably the other of R⁴ and R⁵ that is not the group of formula (IA)is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0 to2; wherein that R⁴ or R⁵ may be optionally substituted on carbon by oneor more R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino.

More preferably the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio,isopropylthio or mesyl; wherein that R⁴ or R⁵ may be optionallysubstituted on carbon by one or more R¹⁶; wherein R¹⁶ is independentlyselected from hydroxy and N,N-dimethylamino.

Particularly the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio,isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino) ethylthio ormesyl.

More particularly the other of R⁴ and R⁵ that is not the group offormula (IA) is methylthio. Preferably the other of R⁴ and R⁵ that isnot the group of formula (IA) is selected from hydrogen, halo,C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0 to 2; wherein that R⁴ orR⁵ may be optionally substituted on carbon by one or more R¹⁶; whereinR¹⁶ is independently selected from hydroxy, carboxy andN,N—(C₁₋₄alkyl)₂amino.

More preferably the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio,ethylthio, isopropylthio or mesyl; wherein that R⁴ or R⁵ may beoptionally substituted on carbon by one or more R¹⁶; wherein R¹⁶ isindependently selected from hydroxy, carboxy and N,N-dimethylamino.

Particularly the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio,carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio,2-(N,N-dimethylamino) ethylthio or mesyl.

In another aspect of the invention, more preferably the other of R⁴ andR⁵ that is not the group of formula (IA) is selected from hydrogen,chloro, bromo, methoxy, isopropoxy, methylthio, ethylthio orisopropylthio; wherein that R⁴ or R⁵ may be optionally substituted oncarbon by one or more R¹⁶; wherein R¹⁶ is independently selected fromhydroxy, carboxy and N,N-dimethylamino.

In another aspect of the invention, particularly the other of R⁴ and R⁵that is not the group of formula (IA) is selected from hydrogen, chloro,bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio,isopropylthio, 2-hydroxyethylthio or 2-(N,N-dimethylamino) ethylthio.

In another aspect of the invention, more particularly the other of R⁴and R⁵ that is not the group of formula (IA) is bromo or chloro.

In another aspect of the invention, more particularly the other of R⁴and R⁵ that is not the group of formula (IA) is methoxy.

In one aspect of the invention, preferably Ring A is aryl.

In another aspect of the invention, preferably Ring A is heteroaryl.

When Ring A is aryl, preferably Ring A is phenyl.

When Ring A is heteroaryl, preferably Ring A is thienyl or indolyl.

Preferably Ring A is aryl or heteroaryl; wherein Ring A is optionallysubstituted by one or more substituents selected from R¹⁷; wherein R¹⁷is selected from halo, hydroxy or Cl 4alkyl; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein R²¹ isselected from halo.

Preferably X is —O.

More preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A isoptionally substituted by one or more substituents selected from halo,hydroxy or trifluoromethyl.

Particularly Ring A is selected from phenyl, 4-hydroxyphenyl,thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,2,3-dihydroxyphenyl or indol-3-yl. More particularly Ring A is phenyl.

In another aspect of the invention, preferably Ring A is aryl orheteroaryl; wherein Ring A is optionally substituted by one or moresubstituents selected from R¹⁷; wherein R¹⁷ is selected from halo,hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷ may be optionallysubstituted on carbon by one or more R²¹; wherein R²¹ is selected fromhalo.

In another aspect of the invention, more preferably Ring A is phenyl,thienyl or indolyl; wherein Ring A is optionally substituted by one ormore substituents selected from halo, hydroxy, methoxy ortrifluoromethyl.

In another aspect of the invention, particularly Ring A is selected fromphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl,4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,2,3-dihydroxyphenyl or indol-3-yl.

In a further aspect of the invention, particularly Ring A is selectedfrom phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl,4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,4-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.

Preferably R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl.

More preferably R⁷ is hydrogen, methyl or phenyl.

Particularly R⁷ is hydrogen.

In one aspect of the invention, preferably R⁸ is hydrogen.

In another aspect of the invention, preferably R⁸ is C₁₋₄alkyl.

In another aspect of the invention, more preferably R⁸ is hydrogen ormethyl.

In one aspect of the invention, preferably R⁹ is hydrogen.

In another aspect of the invention, preferably R⁹ is C₁₋₄alkyl.

In another aspect of the invention, more preferably R⁹ is hydrogen ormethyl.

Preferably R¹⁰ is hydrogen.

In one aspect of the invention, preferably R¹¹ is carboxy, sulpho,sulphino, phosphono, —P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)),—P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) areindependently selected from C₁₋₆alkyl.

In another aspect of the invention, preferably R¹¹ is a group of formula(IB) (as depicted above).

Preferably R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB)(as depicted above). More preferably R¹¹ is carboxy, —P(O)(OH)(OEt) or agroup of formula (IB) (as depicted above).

In another aspect of the invention, preferably R¹¹ is carboxy, sulpho,—P(O)(OH)(OR^(c)) wherein R^(c) is selected from C₁₋₄alkyl or a group offormula (IB) (as depicted above).

Preferably Y is —NH— or —NHC(O)—.

More preferably Y is —NHC(O)—.

In one aspect of the invention, preferably R¹² is hydrogen.

In another aspect of the invention, preferably R¹² is C₁₋₄alkyl.

In another aspect of the invention, more preferably R¹² is hydrogen ormethyl.

Preferably R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy.

More preferably R¹³ is hydrogen, methyl or phenyl; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy.

Particularly R¹³ is hydrogen, hydroxymethyl or phenyl.

More particularly R¹³ is hydrogen or hydroxymethyl.

In another aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionally substituted by oneor more substituents selected from R²⁰; wherein R²⁰ is hydroxy, carboxy,carbocyclyl or amino; wherein R²⁰ may be optionally substituted oncarbon by one or more R²²; R²² is hydroxy.

In another aspect of the invention, more preferably R¹³ is hydrogen,methyl, ethyl, butyl or phenyl; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein R²⁰ is hydroxy,carboxy, phenyl or amino; wherein R²⁰ may be optionally substituted oncarbon by one or more R²²; R²² is hydroxy.

In another aspect of the invention, particularly R¹³ is hydrogen,hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In a further aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionally substituted by oneor more substituents selected from R²⁰; wherein R²⁰ is hydroxy, carboxy,carbocyclyl, heterocyclyl or amino; wherein R²⁰ may be optionallysubstituted on carbon by one or more R²²; R²² is hydroxy.

In a further aspect of the invention, more preferably R¹³ is hydrogen,methyl, ethyl, butyl or phenyl; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein R²⁰ is hydroxy,carboxy, phenyl, imidazolyl or amino; wherein R²⁰ may be optionallysubstituted on carbon by one or more R²²; R²² is hydroxy.

In a further aspect of the invention, particularly R¹³ is hydrogen,hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl,imidazol-5-ylmethyl or phenyl.

In another further aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl, carbocyclyl or R²³; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein R²⁰ is hydroxy,C₁₋₄alkylS(O) a wherein a is 0, C₁₋₄alkoxy, amino, carbocyclyl,heterocyclyl or mercapto; wherein R²⁰ may be independently optionallysubstituted on carbon by one or more R²²; R²² is selected from hydroxy;and R²³ is carboxy.

In another further aspect of the invention, more preferably R¹³ ishydrogen, methyl, ethyl, butyl or phenyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl ormercapto; wherein R²⁰ may be independently optionally substituted oncarbon by one or more R²²; R²² is selected from hydroxy; and R²³ iscarboxy.

In another further aspect of the invention, particularly R¹³ ishydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl,methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl,imidazol-5-ylmethyl or phenyl.

In another aspect more particularly R¹³ is methylthiomethyl,methylsulphinylmethyl or methylsulphonylmethyl.

Preferably R¹⁴ is hydrogen.

In another aspect of the invention, preferably R¹⁴ is selected fromhydrogen, C₁₋₄alkyl or carbocyclyl; wherein said C₁₋₄alkyl orcarbocyclyl may be optionally substituted by one or more substituentsselected from R²⁰; and R²⁰ is hydroxy.

In another aspect of the invention, more preferably R¹⁴ is selected fromhydrogen, methyl or phenyl; wherein said methyl or phenyl may beoptionally substituted by one or more substituents selected from R²⁰;and R²⁰ is hydroxy.

In another aspect of the invention, particularly R¹⁴ is hydrogen, phenylor hydroxymethyl. Particularly R¹⁵ is carboxy or sulpho.

In one aspect of the invention, more particularly R¹⁵ is carboxy.

In another aspect of the invention, more particularly R¹⁵ is sulpho.

Preferably R¹⁵ is carboxy, sulpho, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₄alkyl.

More preferably R¹⁵ is carboxy, sulpho, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from methyl or ethyl.

Preferably R¹⁵ is carboxy, sulpho, —P(O)(OEt)(OEt), —P(O)(OH)(OEt),—P(O)(OH)(Me) or —P(O)(OEt)(Me).

Preferably R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH) (R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₄alkyl or R¹⁵ is agroup of formula (IC) (as depicted above).

More preferably R¹⁵ is carboxy, sulpho, phosphono,—P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or—P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selectedfrom methyl or ethyl or R¹⁵ is a group of formula (IC) (as depictedabove).

Preferably R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OEt)(OEt),—P(O)(Ot-Bu)(Ot-Bu), —P(O)(OH)(OEt), —P(O)(OH)(Me) or —P(O)(OEt)(Me) orR¹⁵ is a group of formula (IC) (as depicted above).

In one aspect of the invention, preferably R¹⁵ is carboxy.

In another aspect of the invention, preferably R¹⁵ is sulpho.

In another aspect of the invention, preferably R¹⁵ is —P(O)(OH)(OEt).

In another aspect of the invention, preferably R¹⁵ is —P(O)(OH)(Me).

In another aspect of the invention, preferably R¹⁵ is —P(O)(OEt)(Me).

In one aspect of the invention, preferably R²⁴ is hydrogen.

In another aspect of the invention, preferably R²⁴ is C₁₋₄alkyl.

Preferably R²⁵ is hydrogen.

Preferably R²⁶ is carboxy.

Preferably p is 1 or 2; wherein the values of R¹³ may be the same ordifferent.

In one aspect of the invention, more preferably p is 1.

In another aspect of the invention, more preferably p is 2; wherein thevalues of R¹³ may be the same or different.

In a further aspect of the invention, more preferably p is 3; whereinthe values of R¹³ may be the same or different.

In one aspect of the invention, preferably q is 0.

In a further aspect of the invention, preferably q is 1.

In one aspect of the invention, preferably r is 0.

In one aspect of the invention, more preferably r is 1.

In another aspect of the invention, more preferably r is 2; wherein thevalues of R¹⁴ may be the same or different.

In a further aspect of the invention, more preferably r is 3; whereinthe values of R¹⁴ may be the same or different.

Preferably m is 0.

In another aspect of the invention, preferably m is 0 or 1.

Preferably n is 1.

In another aspect of the invention, preferably n is 1 or 2.

Preferably z is 1.

The group of formula (IA) wherein R⁷ is hydrogen, methyl or phenyl, n is1, Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionallysubstituted by one or more substituents selected from halo, hydroxy ortrifluoromethyl, m is 0 and R⁹ is carboxy, —P(O)(OH)(OR^(c)) or a groupof formula (IB).

The group of formula (IA) wherein: X is —O—.

Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionallysubstituted by one or more substituents selected from halo, hydroxy,methoxy or trifluoromethyl;

R⁷ is hydrogen, methyl or phenyl;

R⁸ is hydrogen or methyl;

R⁹ is hydrogen or methyl;

R¹⁰ is hydrogen;

m is 0-2 wherein the values of R¹⁰ may be the same or different; and R¹¹is carboxy, —P(O)(OH)(OEt) or a group of formula (IB) (as depicted inclaim 1); The group of formula (IB) wherein R¹⁰ is hydrogen,hydroxymethyl or phenyl, p is 1 or 2; wherein the values of R¹⁰ may bethe same or different and R¹¹ is carboxy or sulpho.

The group of formula (IB) wherein:

R¹² is hydrogen or methyl;

R¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;R²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto;wherein R²⁰ may be independently optionally substituted on carbon by oneor more hydroxy; R²³ is carboxy; Y is —NH— or —NHC(O)—; R¹⁴ is selectedfrom hydrogen, methyl or phenyl; wherein said methyl or phenyl may beoptionally substituted by one or more substituents selected fromhydroxy; R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from methyl or ethyl or R¹⁸is a group of formula (IC) (as depicted in claim 1);

p is 1-3 wherein the values of R¹³ may be the same or different;

q is 0-1; and

r is 0-3 wherein the values of R¹⁴ may be the same or different;

The group of formula (IC) wherein

R²⁴ is hydrogen;

R²⁵ is hydrogen;

R²⁶ is carboxy; and

z is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in a further aspect of the invention, there is provided acompound of formula (I) as depicted above wherein:

R¹ and R² are independently selected from ethyl or butyl;

R³ and R⁶ are hydrogen;

R⁴ is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0to 2; wherein that R⁴ may be optionally substituted on carbon by one ormore R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino;

R⁵ is a group of formula (IA);

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷; wherein

R¹⁷ is selected from halo, hydroxy or C₁₋₄alkyl; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein

R²¹ is selected from halo;

R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB) (asdepicted above);

R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionallysubstituted by one or more substituents selected from R²⁰; wherein

R²⁰ is hydroxy;

R¹⁵ is carboxy or sulpho;

p is 1 or 2; wherein the values of R¹³ may be the same or different;

m is 0; and

n is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) as depicted above wherein:

R¹ and R² are both butyl or one of R¹ and R² is ethyl and the other isbutyl;

R⁴ is methylthio;

R⁵ is a group of formula (IA) (as depicted above);

R³ and R⁶ are hydrogen;

Ring A is phenyl;

R⁷ is hydrogen;

R¹¹ is a group of formula (IB) (as depicted above);

R¹³ is hydrogen or hydroxymethyl;

R¹⁵ is carboxy or sulpho;

p is 1 or 2; wherein the values of R¹³ may be the same or different;

m is 0;

n is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional further aspect of the invention, there isprovided a compound of formula (I) as depicted above wherein:

R¹ and R² are independently selected from ethyl or butyl;

R³ and R⁶ are hydrogen;

R⁴ is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0to 2; wherein that R⁴ may be optionally substituted on carbon by one ormore R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino;

R⁵ is a group of formula (IA);

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl;

R⁸ is hydrogen or methyl;

R⁹ is hydrogen or methyl;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB) (asdepicted above);

X is —NH— or —NHC(O)—;

R¹² is hydrogen or methyl;

R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionallysubstituted by one or more substituents selected from R²⁰;

R¹⁴ is hydrogen;

R¹⁵ is carboxy or sulpho;

R¹⁷ is selected from halo, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷may be optionally substituted on carbon by one or more R²¹;

R²⁰ is hydroxy, carboxy, carbocyclyl or amino; wherein R²⁰ may beoptionally substituted on carbon by one or more R²²;

R²¹ is selected from halo;

R²² is hydroxy;

p is 1-3; wherein the values of R¹³ may be the same or different.

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different; andwherein if q is 1, r is not 0;

m is 0-2; and

n is 1-3;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in another additional further aspect of the invention, thereis provided a compound of formula (I) as depicted above wherein:

R¹ and R² are independently selected from C₁₋₄alkyl; R^(x) and R^(y) areboth hydrogen;

R^(z) is selected from halo, amino, C₁₋₆alkyl, C₁₋₆alkoxycarbonylaminoor N′—(C₁₋₆alkyl)ureido;

v is 0 or 1;

R³ and R⁶ are hydrogen;

one of R⁴ and R⁵ is a group of formula (IA) (as depicted above) and theother is selected from hydrogen, halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a)wherein a is 0 to 2; wherein that R⁴ or R⁵ may be optionally substitutedon carbon by one or more R¹⁶; wherein R¹⁶ is independently selected fromhydroxy, carboxy and N,N—(C₁₋₄alkyl)2amino;

X is —O—;

R⁷ is hydrogen, methyl or phenyl;

R⁶ is hydrogen or methyl;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷; wherein R¹⁷ is selectedfrom halo, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein R²¹ isselected from halo;

R⁹ is hydrogen or methyl;

R¹⁰ is hydrogen;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) wherein R^(c) is selected fromC₁₋₄alkyl or a group of formula (IB) (as depicted above);

R¹² is hydrogen or methyl;

Y is —NH— or —NHC(O)—;

R¹³ is hydrogen, C₁₋₄alkyl, carbocyclyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy, C₁₋₄alkylS(O)_(a) wherein a is 0, C₁₋₄alkoxy,amino, carbocyclyl, heterocyclyl or mercapto; wherein R²⁰ may beindependently optionally substituted on carbon by one or more R²²; R²²is selected from hydroxy; and R²³ is carboxy;

R¹⁴ is selected from hydrogen, C₁₋₄alkyl or carbocyclyl; wherein saidC₁₋₄alkyl or carbocyclyl may be optionally substituted by one or moresubstituents selected from R²⁰; and R²⁰ is hydroxy;

R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₄alkyl or R¹⁵ is agroup of formula (IC) (as depicted above);

R²⁴ is hydrogen;

R²⁵ is hydrogen;

R²⁶ is carboxy;

p is 1-3; wherein the values of R¹³ may be the same or different;

q is 0-1;

r is 0-3; wherein the values of R¹⁴ may be the same or different;

m is 0-2; wherein the values of R¹⁰ may be the same or different;

n is 1-2; wherein the values of R⁷ may be the same or different;

z is 0-1; wherein the values of R²⁵ may be the same or different;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

An aspect of the invention is a compound of formula II

wherein

M is CH₂ or NH;

R¹ is H or hydroxy;

R² is H, CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂OH, —CH₂OCH₃, —CH(OH)CH₃, —CH₂SCH₃, or—CH₂CH₂SCH₃;

for use in the prophylaxis or treatment of a liver disease.

Examples of useful substances in accordance with the invention are:

-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}    carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,    3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)    carbamoyl]benzyl} carbamoylmethoxy)-2,3,4,    5-tetrahydro-1,5-benzothiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-d    butyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxybutyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)    carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,    3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxypropyl)    carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,-   1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine    and-   1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)    carbamoyl] methyl}    carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.

Compounds of formula (I) or formula (II) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess IBAT inhibitoryactivity. The invention relates to any and all tautomeric forms of thecompounds of the formula (I) or formula (II) that possess IBATinhibitory activity.

The invention also relates all possible isomers of the compounds of theinvention such as, optical and/or geometrical, pure or as a mixture, inall proportions, of the said compounds of formulas I and II and thosespecifically mentioned and the possible tautomeric forms

In certain embodiments, compounds described herein have one or morechiral centres. As such, all stereoisomers are envisioned herein. Invarious embodiments, compounds described herein are present in opticallyactive or racemic forms. It is to be understood that the compounds ofthe present invention encompasses racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.Preparation of optically active forms is achieve in any suitable manner,including by way of non-limiting example, by resolution of the racemicform by recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase. In some embodiments,mixtures of one or more isomer are utilized as the therapeutic compounddescribed herein. In certain embodiments, compounds described herein,contains one or more chiral centres. These compounds are prepared by anymeans, including enantioselective synthesis and/or separation of amixture of enantiomers and/or diastereomers. Resolution of compounds andisomers thereof is achieved by any means including, by way ofnon-limiting example, chemical processes, enzymatic processes,fractional crystallization, distillation, chromatography, and the like.

The compounds may exist in free-acid or free-base form, or in apharmaceutically acceptable salt form. In certain embodiments, acompound described herein exists in an unsolvated or solvated form,wherein solvated forms comprise any pharmaceutically acceptable solvent,e.g., water, ethanol, and the like.

The invention further regards a composition comprising at least one IBATinhibitor of Formula (I) or Formula (II), for use in the prophylaxisand/or treatment of a liver disease.

An aspect of the invention is the use of a compound of Formula (I) orFormula (II), for the preparation of a medicine for the treatment of aliver disease.

An IBAT inhibitor of Formula I or Formula II) may be used together withat least one other therapeutically active compound as described herein,in the preparation of a medicament for the prophylactic and/ortherapeutic treatment of a liver disease.

Liver Diseases

Liver disease is herein defined as any Bile Acid (BA) dependent diseasein the liver and in organs connected therewith, such as the pancreasportal vein, the liver parenchyma, the intrahepatic biliary tree, theextrahepatic biliary tree, and the gall bladder.

Ileal bile acid transporter (IBAT) is the main mechanism forre-absorption of bile acids from the GI tract. Partial or full blockadeof that mechanism will result in lower concentration of bile acids inthe small bowel wall, the portal vein, the liver parenchyma, theintrahepatic biliary tree, the extrahepatic biliary tree, and in thegall bladder. Diseases which may benefit from partial or full blockadeof the IBAT mechanism may be those having a primary pathophysiologicaldefect, causing or having symptoms of too high concentration of bileacids in serum and in the above organs.

An aspect of the invention is a compound of Formula (I) or Formula (II)as defined above, for use in the prophylaxis or treatment of liverparenchyma; an Inherited metabolic disorder of the liver; Bylersyndrome; a primary defect of bile acid (BA) synthesis such ascerebrotendinous, or xanthomatosis; a secondary defect such asZellweger's syndrome, neonatal hepatitis, cystic fibrosis,manifestations in the liver, ALGS (Alagilles syndrome), PFIC(progressive familial intrahepatic cholestasis, autoimmune hepatitis,primary biliary cirrhosis (PBC), liver fibrosis, non alcoholic fattyliver disease, NAFLD/NASH, portal hypertension, general cholestasis suchas in jaundice due to drugs or during pregnancy, intra and extrahepaticcholestasis such as hereditary forms of cholestasis such as PFIC1,Primary sclerosing cholangitis, gall stones and choledocholithiasis,malignancy causing obstruction of the biliary tree, symptoms(scratching, pruritus) due to cholestasis/jaundice, pancreatitis,chronic autoimmune liver disease leading to progressive cholestasis, orpruritus of cholestatic liver disease.

An aspect of the invention is a compound of Formula (I) or Formula (II)as defined above, for use in the prophylaxis or treatment of a hepaticdisorder or a hepatic related condition, fatty liver, hepatic steatosis,non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fattyliver, fatty liver of pregnancy, drug-induced hepatitis, iron overloaddisorders, hepatic fibrosis, hepatic cirrhosis, hepatoma, viralhepatitis and problems in relation to tumours and neoplasmas of theliver, of the biliary tract and of the pancreas.

Combination with Other Active Substances

An aspect of the invention is an IBAT inhibitor according to formula (I)or Formula (II) as defined above, in combination with at least one othertherapeutically active substance. The at least one other therapeuticallyactive substance may be an IBAT inhibitor compound.

Incretines and Hormones Produced by the L Cells

The at least one other therapeutically active substance may be anIncretine or a hormone produced by the L cells.

In an aspect of the invention, the at least one other therapeuticallyactive substance is a L-cell endocrine peptide enhancer such as a GLP-1enhancer. Examples of a GLP-1 enhancer useful in accordance with theinvention are GLP-1, a GLP-1 secretion enhancer, a GLP-1 degradationinhibitor, or a combination thereof.

In an aspect of the invention, the L-cell endocrine peptide enhancer isa GLP-2 enhancer such as GLP-2, a GLP-2 secretion enhancer, a GLP-2degradation inhibitor, or a combination thereof.

In an aspect of the invention the L-cell endocrine peptide enhancer is aPYY enhancer such as an oxyntomodulin enhancer.

Incretin Mimetics

In an aspect of the invention, the at least one other therapeuticallyactive substance is an incretin mimetic such as exenatide (Byetta®).

One aspect of the invention is an oral combination of an IBAT inhibitorof Formula (I) or Formula (II) as disclosed herein and a DPP-IVinhibitor.

Enteroendocrine Peptides

In an aspect of the invention, the at least one other therapeuticallyactive substance is an enteroendocrine peptide such as GLP-1 or GLP-1analogs, for example Taspoglutide® (Ipsen), or the like.

Combination Therapy with an IBAT Inhibitor and a DPP-IV Inhibitor

In an aspect of the invention, the at least one other therapeuticallyactive substance is a DPP-IV inhibitor.

One aspect of the invention is a combination of an IBAT-inhibitor andmetformin and/or sitagliptin (Janumet®) and/or DPP-IV inhibitorssuitable for use with the methods described herein include but are notlimited to(2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]-acetyl}pyrrolidine-2-carbonitrile(vildagliptin),(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one(sitagliptin),(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[−3.1.0]hexane-3-carbonitrile(saxagliptin), and2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidi-n-1(2H)-yl}methyl)benzonitrile(alogliptin).

TGR5 Receptor Modulators

In one aspect of the invention, the at least one other therapeuticallyactive substance is a TGR5 agonist. TGR5 modulators (e.g. agonists)include, but are not limited to, the compounds described in WO2008/091540, WO 2008/067219 and U.S. Appl. No. 2008/0221161.

Thiazolidinediones

In one embodiment of the invention, the at least one othertherapeutically active substance is a thiazolidinedione such asRosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin),MCC-555, rivoglitazone, ciglitazone or the like.

Combination Therapy with an IBAT INHIBITOR, a Biliary Shunt and a DPP-IVInhibitor

In one embodiment of the invention, an IBAT INHIBITOR of Formula (I) orFormula (II) as described herein, is administered in combination with aDPP-IV inhibitor and/or a biliary shunt. Examples of biliary shuntsinclude but are not limited to shunts described in WO 2007/0050628,which disclosure is incorporated herein by reference.

As used herein, the term “additive effect” describes the combined effectof two (or more) pharmaceutically active agents that is equal to the sumof the effect of each agent given alone. A synergistic effect is one inwhich the combined effect of two (or more) pharmaceutically activeagents is greater than the sum of the effect of each agent given alone.Any suitable combination of an ASBTI with one or more of theaforementioned other active ingredients and optionally with one or moreother pharmacologically active substances is contemplated as beingwithin the scope of the methods described herein.

In some embodiments, the particular choice of compounds depends upon thediagnosis of the attending physicians and their judgment of thecondition of the individual and the appropriate treatment protocol. Thecompounds are optionally administered concurrently (e.g.,simultaneously, essentially simultaneously or within the same treatmentprotocol) or sequentially, depending upon the nature of the disease,disorder, or condition, the condition of the individual, and the actualchoice of compounds used. In certain instances, the determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is based on anevaluation of the disease being treated and the condition of theindividual.

In some embodiments, therapeutically-effective dosages vary when thedrugs are used in treatment combinations. Methods for experimentallydetermining therapeutically-effective dosages of drugs and other agentsfor use in combination treatment regimens are described in theliterature.

In some embodiments of the combination therapies described herein,dosages of the co-administered compounds vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein is optionally administered either simultaneously with thebiologically active agent(s), or sequentially. In certain instances, ifadministered sequentially, the attending physician will decide on theappropriate sequence of therapeutic compound described herein incombination with the additional therapeutic agent.

The multiple therapeutic agents (at least one of which is a therapeuticcompound described herein) are optionally administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsare optionally provided in a single, unified form, or in multiple forms(by way of example only, either as a single pill or as two separatepills). In certain instances, one of the therapeutic agents isoptionally given in multiple doses. In other instances, both areoptionally given as multiple doses. If not simultaneous, the timingbetween the multiple doses is any suitable timing, e.g., from more thanzero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned (including two or more compounds described herein).

In certain embodiments, a dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors. These factors include the disorderfrom which the subject suffers, as well as the age, weight, sex, diet,and medical condition of the subject. Thus, in various embodiments, thedosage regimen actually employed varies and deviates from the dosageregimens set forth herein.

In some embodiments, the pharmaceutical agents which make up thecombination therapy described herein are provided in a combined dosageform or in separate dosage forms intended for substantially simultaneousadministration. In certain embodiments, the pharmaceutical agents thatmake up the combination therapy are administered sequentially, witheither therapeutic compound being administered by a regimen calling fortwo-step administration. In some embodiments, two-step administrationregimen calls for sequential administration of the active agents orspaced-apart administration of the separate active agents. In certainembodiments, the time period between the multiple administration stepsvaries, by way of non-limiting example, from a few minutes to severalhours, depending upon the properties of each pharmaceutical agent, suchas potency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent.

The invention also regards IBAT inhibitor compounds described herein incombination with at least one bile acid binder e.g. a resin such ascholestyramine, cholestipol and colesevelam.

Bile Acid Binders (Bile Acid Sequestrants, Resins)

In one embodiment of the invention, an IBAT inhibitor of formula (I) orFormula (II) as defined above, may be administered as a pharmaceuticalformulation also comprising at least one bile acid binder, saidformulation being designed to deliver the bile acid binder in the colonand the IBAT inhibitor in the small intestine.

Examples of useful bile acid binders according to the invention areCholestyramine, which is a hydrophilic polyacrylic quaternary ammoniumanion exchange resin, known to be effective in reducing bloodcholesterol levels. Cholestyramine, and various compositions includingcholestyramine, are described, for example, in British Pat Nos. 929,391and 1,286,949; and U.S. Pat. Nos. 3,383,281; 3,308,020; 3,769,399;3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354;4,874,744; 4,895,723; 5,695,749; and 6,066,336. Cholestyramine iscommercially available from Novopharm, USA Inc (Questrans Light),Upsher-Smith (PREVALITE (D), and Apothecon. As used herein,“cholestyramine” includes any such composition comprisingcholestyramine, or pharmaceutically acceptable salts thereof. These arealso called Questrans™

Questran Light Questrans Light (cholestyramine) is a non-absorbableanion binding resin FDA approved for the treatment ofhypercholesterolemia.

An amine polymer having a first substituent, bound to a first amine ofthe amine polymer, that includes a hydrophobic aliphatic moiety, and asecond substituent, bound to a second amine of the amine polymer, thatincludes an aliphatic quaternary amine-containing moiety as described inU.S. Pat. Nos. 5,693,675 and 5,607,669.

The salt of an alkylated and cross linked polymer comprising thereaction product of: (a) one or more cross linked polymers, or salts andcopolymers thereof having a repeat unit selected from the groupconsisting of: (NR—CH₂CH₂)n (2) and(NR—CH₂CH₂—NR—CH₂CH₂—NR—CH₂CHOH—CH₂)n (3) where n is a positive integerand each R, independently, is H or a C1-C8 alkyl group; (b) at least onealiphatic alkylating agent, said reaction product characterized in that:(i) at least some of the nitrogen atoms in said repeat units unreactedwith said alkylating agent; (ii) less than 10 mol percent of thenitrogen atoms in said repeat units reacting with said alkylating agentforming quaternary ammonium units; and (iii) a fixed positive charge andone or more counter ions, such as Colesevelam and colesevelamhydrochloride.

Useful bile acid binders in accordance with the invention are resins,such as cholestyramine and cholestipol. One advantage is that the doseof bile acid binder might be kept lower than the therapeutic dose fortreatment of cholesterolaemia in single treatment comprising solely abile acid binder. By a low dose of bile acid binder any possible sideeffects caused by poor tolerance of the patient to the therapeutic dosecould also be avoided.

Another useful bile acid binder is a water insoluble non-toxic polymericamine having a molecular weight in excess of 3,000, having the propertyof binding at least 30% of the available glycocholic acid within 5minutes when exposed to an aqueous solution of an equal weight of saidacid, having a polymer skeleton inert to digestive enzymes, and having awater content greater than 65% after equilibration with air at 100%relative humidity, e.g., cholestipol described in U.S. Pat. No.3,383,281,

In a further aspect of the invention a suitable bile acid binder is oneof cholestyramine, cholestipol or colesevelam.

A preferred aspect of the present invention is the use of colesevelam asthe bile acid binder.

The compositions of the invention may further comprise statins e.g anHMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, in associationwith a pharmaceutically acceptable diluent or carrier.

One embodiment of the invention relates to a combined oralpharmaceutical formulation comprising an IBAT inhibitor compound offormula (I) or Formula (II) as defined above or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand a bile acid binder or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, said formulation beingdesigned to deliver the bile acid binder in the colon and the IBATinhibitor in the small intestine.

One embodiment of the present invention is a pharmaceutical formulationcomprising a core of a bile acid binder formulated for release in thecolon, surrounded by an outer layer comprising an IBAT inhibitor offormula (I) or Formula (II) as defined above, and formulated forimmediate release or for delayed release in the distal jejunum or theproximal ileum.

Statins

In another aspect of the invention, an IBAT inhibitor compound e.g. acompound of formula (I) or formula (II) as defined above or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl) amino] pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof. Aparticular statin is atorvastatin, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. A moreparticular statin is atorvastatin calcium salt. A further particularstatin is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl) amino] pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.Other particular statin are rosuvastatin calcium salt and pitavastatin(HMG Co A reductase).

In an additional aspect of the invention, the compound of formula (I) orformula (II) as defined above, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof may be administeredin association with an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and/or a bile acid binder thereby avoiding a possiblerisk of excess of bile acids in colon caused by the inhibition of theileal bile acid transport system. An excess of bile acids in thevisceral contents may cause diarrhoea. Thus, the present invention alsoprovides a treatment of a possible side effect such as diarrhoea inpatients during therapy comprising a compound of formula (I) or formula(II) as defined above, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof will by its actiondecrease the endogenous cholesterol available for the bile acidsynthesis and have an additive effect in combination with a compound offormula (I) or formula (II) as defined above, or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof onlipid lowering.

The composition may further comprise a PPAR alpha and/or gamma agonist,or a pharmaceutically acceptable salt thereof.

A CETP (cholesteryl ester transfer protein) inhibitor, for example thosereferenced and described in WO 00/38725 page 7 line 22-page 10, line 17which are incorporated herein by reference.

A cholesterol absorption antagonist for example azetidinones such as SCH58235 and those described in U.S. Pat. No. 5,767,115 which areincorporated herein by reference;

MTP (microsomal transfer protein) inhibitor for example those describedin Science, 282, 751-54, 1998 which are incorporated herein byreference;

A fibric acid derivative; for example clofibrate, gemfibrozil,fenofibrate, ciprofibrate and bezafibrate;

A nicotinic acid derivative, for example, nicotinic acid (niacin),acipimox and niceritrol;

A phytosterol compound for example stanols;

Probucol;

An anti-obesity compound for example orlistat (EP 129,748) andsibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);

An antihypertensive compound for example an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin II receptor antagonist, anadrenergic blocker, an alpha adrenergic blocker, a beta adrenergicblocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant,calcium channel blocker, a diuretic or a vasodilator;

Insulin;

Sulphonylureas including glibenclamide and/or tolbutamide.

Biguanides

In some embodiments, the additional therapeutic agent is a biguanide. Insome instances, biguanides reduce blood and/or plasma glucose levels.Examples of biguanides include and are not limited to metformin,buformin, phenformin, proguanil or the like.

Acarbose;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof, optionally together with a pharmaceuticallyacceptable diluent or carrier to a warm-blooded animal, such as man inneed of such therapeutic treatment.

Angiotensin II Antagonists

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula (I) include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

PPAR alpha and/or gamma and/or delta agonists or a pharmaceuticalacceptable salt thereof.

In another aspect of the invention, the IBAT inhibitor compound, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (inparticular the compounds described in the patent applications listed onpage 634) and J Med Chem, 2000, 43, 527 which are all incorporatedherein by reference. Particularly a PPAR alpha and/or gamma agonistrefers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578,troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone,BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207,L-796449, L-165041 and GW 2433.

Particularly a PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl} ethoxy) phenyl]propanoic acid and pharmaceutically acceptable salts thereof.

According to one embodiment the substances of the invention are usedtogether with one or more antidiabetics hypoglycemic active ingredients,cholesterol absorption inhibitors, PPAR delta agonists, fibrates, MTPinhibitors, bile acid absorption inhibitors, polymeric bile acidadsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants,lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalenesynthetase inhibitors, lipoprotein(a) antagonists, HM74A receptoragonists, lipase inhibitors, insulins, sulfonylureas, biguanides,meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, activeingredients which act on the ATP-dependent potassium channel of the betacells, glycogen phosphorylase inhibitors, glucagon receptor antagonists,activators of glucokinase, inhibitors of gluconeogenesis, inhibitors offructose-1,6-bisphosphatase, modulators of glucose transporter 4,inhibitors of glutamine-fructose-6-phosphate amidotransferase,inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase,inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvatecarboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitorsof protein kinase C beta, endothelin-A receptor antagonists, inhibitorsof I kappaB kinase, modulators of the glucocorticoid receptor, CARTagonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNFagonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta 3agonists, CB1 receptor antagonists, MSH (melanocyte-stimulating hormone)agonists, CCK agonists, serotonin reuptake inhibitors, mixedserotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptinagonists, DA agonists (bromocriptine, Doprexin), lipase/amylaseinhibitors, PPAR modulators, RXR modulators or TR-beta agonists oramphetamines.

One aspect of the invention is a method for the treatment of a liverdisease, whereby an IBAT inhibitor of Formula (I) or Formula (II) asdefined above is brought into contact with the distal ileum of anindividual in need of such treatment.

In one embodiment of the invention, an IBAT inhibitor of Formula (I) orFormula (II) as defined above, is administered in combination with asecond therapeutic agent selected from a DPP-IV inhibitor, athiazolidinedione, or an analogue thereof, or a TGR5 agonist.

In certain embodiments, IBAT inhibitor compounds described herein arecombined with or utilized in combination with one or more of thefollowing therapeutic agents in any combination: insulin,insulin-mimetics, DPP-IV inhibitors, or TGR5 modulators.

Further active substances to be combined with one or more IBATinhibitors of the invention may be chosen from one or more of thefollowing substances:

Ursodeoxycholic acid; nor-ursodeoxycholic acid; Rifampicin and relatedrifamycin derivatives as described in U.S. Pat. No. 3,342,810; opiatantagonists such as Naloxone and Naltrexone; serotonin antagonists suchas 5-HT3 receptor antagonists and 5 HT2 antagonists, e.g. Trazodone,Nefazodone, Amoxapine, Clozapine; antihistamines such asBrompheniramine, Chlorpheniramine Dimenhydrinate, Diphenhydramine,Doxylamine Loratadine Cetirizine; serotonin reuptake inhibitors such asCitalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine,lindalpine, Pparoxetine, Sertraline, Zimelidine; corticosteroids such asglucocorticoids and mineralocorticoids e.g. chosen from Hydrocortisone(Cortisol), Cortisone and acetate, Prednisone, Prednisolone,Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone,Beclometasone, Fludrocortisone and acetate, Deoxycorticosterone andacetate (DOCA) Aldosterone.

Examples of PPAR delta agonists are GW-501516 (501516, GSK-516, GW-516,GW-1516; a peroxisome proliferator-activated receptor (PPAR)-deltaagonist, and several other compounds developed from GW-501516, includingGI-262570, GW-0072, GW-7845 and GW-7647.

According to one embodiment the BAT inhibitor may be combined with oneor more of Atreleuton, Eprotirome, Losmapimod, Ezetimibe (SCH58235)Bezafibrate, Fenofibrate, Varespladib, Darapladib, Lomitapide,Implitapide, Rosiglitazone, Dalcetrapib, Anacetrapib, Lorcaserin,Dapagliflozin, Canagliflozin, Sergliflozin ASP-1941 Orlistat,Pioglitazone, Sodelglitazar, Netoglitazone, Indeglitazar, Naveglitazar,Lobeglitazone, Aleglitazar, Bromocriptine, Tesofensine, Monoamine,Alogliptin, Vildagliptin, Saxagliptin, Sitagliptin, Denagliptin,Gemigliptin, Linagliptin, Dutogliptin, Teneligliptin, LC-150444,Laropiprant extended release niacin, Simvastatin ezetimibe, Rosuvastatinfenofibrate, Rosuvastatin ezetimibe and Atorvastatin ezetimibe.

Combinations with Tredaptive, Vytorin and Certriad may be used.

According to one embodiment the IBAT inhibitor may be combined with oneor more of any of the above mentioned other compounds.

According to one embodiment the IBAT inhibitors of the present inventionare combined with at least one other active substance selected fromdipeptidyl peptidase-IV-inhibitors, PPAR γ agonists, statins and bileacid binders in any combination.

According to one embodiment the IBAT inhibitors of the present inventionare combined with at least one DPPIV, at least one PPAR γ agonist, suchas Sitagliptin and Pioglitazon.

According to one other embodiment the IBAT inhibitors of the presentinvention are combined with at least one DPPIV and at least one statine.g. Sitagliptin and Simvastatin.

Another active substance which may be combined with the IBAT inhibitorsof the invention is ursodeoxycholic acid.

According to one embodiment the invention relates to a compositioncomprising one or more IBAT inhibitors of the invention andcholestyramin and/or colesevelam and/or cholestipol.

According to one embodiment the invention relates to a compositioncomprising one or more of the compounds of Example 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13 and 14 and cholestyramin and/or colesevelam and/orcholestipol.

According another embodiment the invention relates to a compositioncomprising one or more of the compounds of1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)-carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 5) and cholestyramin and/or colesevelam and/or cholestipol.

According another embodiment the invention relates to a compositioncomprising one or more of the compounds of1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 13), and cholestyramin and/or colesevelam and/or cholestipol.

According another embodiment the invention relates to a compositioncomprising one or more of the compounds of1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl] methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 14)and cholestyramin and/or colesevelam and/or cholestipol.

Carriers and Excipients

The compositions of the invention may further comprise apharmaceutically acceptable diluent or carrier.

Pharmaceutical compositions may be formulated as known in the art usingone or more physiologically acceptable carriers including, e.g.,excipients and depending on the route of administration chosen.

A carrier includes, in some embodiments, a pharmaceutically acceptableexcipient and is selected on the basis of compatibility with compoundsdescribed herein, such as, compounds of any of Formula I and II, and therelease profile properties of the desired dosage form.

Exemplary carrier materials include, e.g., binders, suspending agents,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, wetting agents, diluents.

Pharmaceutical compositions and carriers are described, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

A mixture of a compound of Formula I and II and possibly also otheractive compounds mentioned herein, with other chemical components, suchas carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients may be formulated into acomposition. In certain embodiments, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to an individual having a disease, disorder, or condition tobe treated. In specific embodiments, the individual is a human. Thecompounds described herein are either utilized separately or incombination with one or more additional therapeutic agents.

In certain embodiments, the pharmaceutical formulations described hereinare administered to an individual in any manner, including one or moreof multiple administration routes, such as, by way of non-limitingexample, oral, parenteral (e.g., intravenous, subcutaneous,intramuscular), intranasal, buccal, topical, rectal, or transdermaladministration routes.

The pharmaceutical compositions described herein are formulated as adosage form. As such, in some embodiments, provided herein does a dosageform comprise a compound described herein, suitable for administrationto an individual. In certain embodiments, suitable dosage forms include,by way of non-limiting example, aqueous oral dispersions, liquids, gels,syrups, elixirs, slurries, suspensions, solid oral dosage forms,aerosols, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

The pharmaceutical solid dosage forms described herein optionallyinclude an additional therapeutic compound described herein and one ormore pharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavouring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In someaspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula I-II. Inone embodiment, a compound described herein is in the form of a particleand some or all of the particles of the compound are coated. In certainembodiments, some or all of the particles of a compound described hereinare microencapsulated. In some embodiments, the particles of thecompound described herein are not microencapsulated and are uncoated.

Method of Treatment

The invention also regards a method for treatment and/or prophylaxis ofa liver disease, in a warm-blooded animal, such as man, in need of suchtreatment and/or prophylaxis comprising administering an effectiveamount of a compound or a composition according to the invention to theindividual.

A method for treating any of the diseases or conditions described hereinin an individual in need of such treatment, may involve administrationof pharmaceutical compositions containing at least one IBAT inhibitordescribed herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to saidindividual.

Dosage Forms

The pharmaceutical solid dosage forms may optionally include additionaltherapeutic compounds and one or more pharmaceutically acceptableadditives such as a compatible carrier, binder, filling agent,suspending agent, flavouring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof. In some aspects, using standardcoating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000), a film coating is providedaround the formulation of the compound of Formula I-II. In oneembodiment, a compound described herein is in the form of a particle andsome or all of the particles of the compound are coated. In certainembodiments, some or all of the particles of a compound described hereinare microencapsulated. In some embodiments, the particles of thecompound described herein are not microencapsulated and are uncoated.

An IBAT inhibitor of Formula I and II may be used in the preparation ofmedicaments for the prophylactic and/or therapeutic treatment of obesityand/or diabetes. A method for treating any of the diseases or conditionsdescribed herein in an individual in need of such treatment, involvesadministration of pharmaceutical compositions containing at least oneIBAT inhibitor described herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to saidindividual.

A dosage form comprises a matrix that allows for controlled release ofan active agent in the distal jejunum, proximal ileum, distal ileumand/or the colon. In some embodiments, a dosage form comprises a polymerthat is pH sensitive (e.g., a MMX™ matrix from Cosmo Pharmaceuticals)and allows for controlled release of an active agent in the ileum and/orthe colon. Examples of such pH sensitive polymers suitable forcontrolled release include and are not limited to polyacrylic polymers(e.g., anionic polymers of methacrylic acid and/or methacrylic acidesters, e.g., Carbopol® polymers, (CAS number 9063-87-0;) that compriseacidic groups (e.g., —COOH, —SO₃H) and swell in basic pH of theintestine (e.g., pH of about 7 to about 8). In some embodiments, adosage form suitable for controlled release in the distal ileumcomprises microparticulate active agent (e.g., micronized active agent).In some embodiments, a non-enzymatically degradingpoly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of anIBAT to the distal ileum. In some embodiments, a dosage form comprisingan IBAT is coated with an enteric polymer (e.g., Eudragit® S-100, casnumber 25086-15-1), cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethylcellulose phthalate, anionic polymers ofmethacrylic acid, methacrylic acid esters or the like) for site specificdelivery to the ileum and/or the colon. In some embodiments, bacteriallyactivated systems are suitable for targeted delivery to the ileum.Examples of micro-flora activated systems include dosage formscomprising pectin, galactomannan, and/or Azo hydrogels and/or glycosideconjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside orthe like) of the active agent. Examples of gastrointestinal micro-floraenzymes include bacterial glycosidases such as, for example,D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase,beta-D-xylopyranosidase or the like.

Coated units may be filled into hard gelatine capsules or mixed withtablet excipients, such as fillers, binders, disintegrants, lubricantsand other pharmaceutically acceptable additives, and be compressed intotablets. The compressed tablet is optionally covered with film-formingagents to obtain a smooth surface of the tablet and further enhance themechanical stability of the tablet during packaging and transport. Sucha tablet coat, which may be applied on a multiple unit tablet or aconventional tablet, may further comprise additives like anti-tackingagents, colorants and pigments or other additives to improve the tabletappearance.

Suitable drugs for the new formulations are IBAT inhibitor compoundssuch as described in the above-discussed documents, hereby incorporatedby references.

The IBAT inhibitor compound could alternatively be a low permeabilitydrug as defined in the Biopharmaceutical Classification System proposedby FDA.

A combination therapy according to the invention should preferablycomprise simultaneously, separately or sequentially administration of anIBAT inhibitor compound and a bile acid binder. The IBAT inhibitor couldpreferably be formulated for ileum delivery and the bile acid bindercould preferably be formulation for colon release.

Dosage

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range5-5000 mg per square meter body area of the animal, i.e. approximately0.1-100 mg or 0.01-50 mg, and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1-250 mg of active ingredient.Preferably a daily dose in the range of 1-50 mg is employed. In anotheraspect a daily dose in the rage of 0.02-20 mg is employed. However thedaily dose will necessarily be varied depending upon the host treated,the particular route of administration, and the severity of the illnessbeing treated.

Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The size of the dose required for the therapeutic or prophylactictreatment will necessarily be varied depending on the host treated, theroute of administration and the severity of the illness being treated. Aunit dose in the range, for example, 1-100, preferably 1-50 isenvisaged. The daily dose can be administered as a single dose ordivided into one, two, three or more unit doses.

A pharmaceutical formulation according to the present invention with atargeted delivery in the gastro intestinal tract provides a reducedsystemic exposure, as can be measured by the area under the drug plasmaconcentration versus time curve (AUC) or 7α-hydroxy-4-cholesten-3-one(C4), while maintaining or even increasing the therapeutic effect, ase.g. measured by serum cholesterol reduction.

A combination therapy comprising an IBAT inhibitor and a bile acidbinder comprises preferably a low daily dose of the bile acid binder,such as less than 5 g of a resin, and more preferably less than 2 g. Adosage form with colon release of the bile acid binder could beconstructed by any of the above described principles for delayed releaseformulations.

A combination therapy comprising an IBAT inhibitor and a bile acidbinder may comprise a low daily dose of the bile acid binder, such asless than 5 g of a resin, and more preferably less than 4, 3, 2 or lessthan 1 g. Suitable ranges may be 0.1-5 g, 0.5-4 g, 1-3 g, 2-4 g, 2-3 gper day. A dosage form with colon release of the bile acid binder couldbe constructed by any of the above described principles for delayedrelease formulations.

A tablet may consist of an inner core of 1-1000 mg, e.g. 200-800 mg,10-400 mg, 10-200 mg or 20-80 mg acid binder in a colonic deliveryformulation and an outer lamina with 1-100 mg, 5-50 mg e.g. 1-20 mg ofan IBAT inhibitor.

The daily dose of IBAT inhibitor and/or bile acid binder can beadministered as a single dose or divided into one, two, three or moreunit doses.

Dosing three times a day with 400 mg of colesevelam in a colonic releaseformulation will give an adequate binding of bile acids in the colon asthe total luminal volume is expected to be about 100 ml, which is inaccordance to an accepted pharmacokinetic calculation volume of 250 to300 ml for the small gut. The daily recommended total dose ofcolesevelam to block bile acid absorption in total gut of humans is 3750mg/day.

Kit

Further, the invention relates to a kit comprising compound or acomposition according to the invention and possibly also an instructionfor use.

According to a further aspect of the present invention there is provideda kit comprising an IBAT inhibitor according to the invention or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an instruction for use.

According to a further aspect of the present invention there is provideda kit comprising an IBAT inhibitor according to the invention or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and any of the above mentioned substances for use incombination, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising: a) an IBAT inhibitor according to the invention or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in a first unit dosage form; b) any of the abovementioned substances for use in combination or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof;in a second unit dosage form; and c) container means for containing saidfirst and second dosage forms.

The following contemplated Examples are intended to illustrate, but inno way limit the scope of the invention. All references cited herein arehereby incorporated by reference in their entirety.

The expression “comprising” as used herein should be understood toinclude, but not be limited to, the stated items.

Example 1

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw.696.89.

This compound is prepared as described in Example 2 of WO3022286.

Example 2

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 709.92.

This compound is prepared as described in Example 2 of WO03106482.

Example 3

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 724.94.

This compound is prepared as described in Example 6 of WO3022286.

Example 4

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 757.01.

This compound is prepared as described in Example 7 of WO3022286.

Example 5

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 740.94.

This compound is prepared as described in Example 29 of WO3022286.

Example 6

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 773.00.

This compound is prepared as described in Example 30 of WO3022286.

Example 7

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 738.97.

This compound is prepared as described in Example 15 of WO3022286.

Example 8

1,1-Dioxo-3,3-dbutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 756.94.

This compound is prepared as described in Example 26 of WO3022286.

Example 9

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 754.97.

This compound is prepared as described in Example 28 of WO3022286.

Example 10

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 710.91.

This compound is prepared as described in Example 5 of WO3022286.

Example 11

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 739.95.

This compound is prepared as described in Example 1 of WO3022286.

Example 12

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 726.91.

This compound is prepared as described in Example 11 of WO3022286.

Example 13

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,Mw. 754.97.

This compound is prepared as described in Example 27 of WO3022286.

Example 14

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl] methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, Mw. 695.90.

This compound is prepared as described in Example 43 of WO0250051.

Example 15

Pharmaceutical Effect Mean Inhibitory Effect (%)

ISBT Hu HEK Uptake SPA 13203 IBAT HUM Ileal Bile Acid Transporter HumanHEK Glycocholic acid Uptake Radiometric—SPA Inhibitor IC50 Mean IC50(nM) was determined for the compounds of examples 1-14

Test System

Animals

Species Mouse; Strain ApoE knock out; Sub strain C57BL/6; Sex Female;Total No. of animals 70; Body weight range 20 g to 22 g; SupplierMöllegaard's Breeding (Skensved, Denmark); Identification method IDcards (bar code).

Acclimatisation At least one week at the Section of Laboratory; AnimalResource at AstraZeneca; Housing conditions Kept five by five in cages(Makrolon III, 7 dm2) in a room with regulated temperature (22° C.),relative humidity (40% to 60%) and a 12/12 hours light/dark cycle. DietFree access to R3 pellets (Lactamin, Vadstena, Sweden) during thehousing and experimental period. Water, free access to tap water duringthe housing and experimental period.

Bedding Sprinkle bedding of aspen wood (Tapvei, Finland).

Experimental Procedures

The animals were orally administered vehicle (n=3) or the compound ofExample 14 (0.156 (n=3), 0.625 (n=3) or 2.5 μmol/kg (n=3)) at 13:00o'clock on the experimental day. Thirty minutes later, a trace amount of⁷⁵SeHCAT (⁷⁵Se-homo-tauro-cholic acid) (0.1 mCi per 0.1 mL per mouse)was orally given to each mouse. Twenty-four hours after ⁷⁵SeHCATadministration, the animals were killed by CO2 inhalation. At sacrifice,the gall bladder and the whole intestine were removed, and the faecesduring the 24-hour period after ⁷⁵SeHCAT administration was collectedfor each mouse. The gamma radioactivities of ⁷⁵SeHCAT in the faeces andin the gall bladder-intestine were separately counted by 1282 CompuGammaCS Gamma counter (Wallac oy, Turku, Finland). The stability as well asthe quantity of the ⁷⁵SeHCAT administered to each mouse, were controlledwith an additional ⁷⁵SeHCAT aliquot following the same experimentalprocess as other tested samples in the study.

Data Analysis

The sum of the gamma counts from both the faeces and the gallbladder-intestine was considered as the total recovered ⁷⁵SeHCAT, whichwas averaged around 85% of the total ⁷⁵SeHCAT administered to eachmouse. Of the recovered radioactivity of ⁷⁵SeHCAT, the percentage of the⁷⁵SeHCAT detected in the faeces was considered as the faecal excretionwhile that in the gall bladder-intestine as body retention. Inhibitoryeffect of the compound of Example 14 on ⁷⁵SeHCAT intestinal absorptionwas calculated following the ⁷⁵SeHCAT body retention and the faecalexcretion, and the ED50 of the compound was estimated following thedose-effect curve.

Results

The mean IBAT inhibitory effect (%) at a dose (μmol/kg): 0.156 wasdetermined for the compounds of examples 1-14 and is reported in Table1.

TABLE 1 % inhibition Mean IC50 Example Structure 0.156 μmol/kg nM 1.

43 0.45 2.

55 0.39 3.

63 0.18 4.

63 0.35 5.

74 0.16 6.

59 — 7.

66 0.36 8.

46 0.11 9.

67 — 10.

68 0.2 11.

63 0.15 12.

63 0.3 13.

68 0.13 14.

28 1.2

Example 16

In Vivo Animal Model of Primary Sclerosing Cholangitis (PSC)

A genetic mice with targeted disruption of the Multidrug resistant Mdr2(Abcb4) gene encoding a canalicular phospholipid flippase (Mdr2−/− mice)spontaneously develop sclerosing cholangitis with macroscopic andmicroscopic features of human Primary sclerosing cholangitis. Bile ductinjury in these mice is linked to defective biliary phospholipidsecretion resulting in an increased concentration of free non-micellarbile acids which subsequently cause bile duct epithelial cell(cholangiocyte) injury, pericholangitis, periductal fibrosis withductular proliferation and finally sclerosing cholangitis. Geneexpression profiling has revealed remarkable similarities betweenMdr2−/− and human PSC. In analogy to the Mdr2−/− mouse model ofsclerosing cholangitis, Multidrug resistant protein MDR3/ABCB4 (thehuman orthologue of rodent Mdr2/Abcb4) defects play a role in thepathogenesis of various cholangiopathies in humans. MDR3 variants play arole as a modifier gene in the pathogenesis of various cholangiopathiessuch as PSC, Primary Biliary cirrhosis (PBC) and adulthood idiopathicductopenia/biliary fibrosis.

Mdr2−/− mice were given daily oral doses of the compound of Example 14by gavage for 2-4 weeks and controls were dosed the vehicle in the sameway. Serum liver tests, liver histology and fibrosis were investigated.The compound of Example 14 improves liver tests, liver histology andfibrosis.

Example 17

A formulation for delayed release of the IBAT inhibitor having thefollowing composition is be prepared:

Substance amount/capsule (mg) IBAT inhibitor compound 10 Example 14 Nonpareil spheres 500 Ethyl cellulose 2 Hydroxypropylmethyl cellulose 10Eudragit L100-55, CAS No: 25212-88-8 25 Triethylcitrate 2.4

The IBAT inhibitor compound of Example 14 is dissolved together withethyl cellulose and hydroxypropyl cellulose in ethanol 99%. The mixtureis then sprayed onto the non-pareil spheres in a fluidized bedapparatus. Thereafter, the pellets are dried and aerated to removeresidual ethanol. The Eudragit L100-55 dispersion with addition oftriethyl citrate is then sprayed onto the drug beads in a fluidized bedapparatus. Subsequently, the coated beads are filled in hard gelatinecapsules after drying and sieving.

Example 18

A formulation for delayed release of the IBAT inhibitor having thefollowing composition is prepared:

Ingredient amount/tablet (mg) IBAT inhibitor compound 10 Example 14Silicon dioxide 200 Povidone K-25 20 Eudragit FS30D, CAS no: 26936-24-330 Microcrystalline cellulose 250 Sodium stearyl fumarate 5

The IBAT inhibitor compound of Example 14 is suspended in water andsprayed onto silicon dioxide cores of a predefined size in a fluidizedbed apparatus. The drug pellets are dried in an oven at 40° C. for 24 h.Thereafter, a layer of Povidone K-25 is applied on the beads from anethanolic solution in a fluidized bed apparatus. A final coat ofEudragit FS30D dispersion is applied thereafter in a fluidized bed. Thecoated beads are mixed with microcrystalline cellulose and sodiumstearyl fumarate in a mixer and subsequently compressed to tablets.

Example 19

An IBAT inhibitor colesevelam combination tablet with immediate releaseof the IBAT inhibitor and colon release of the bile acid binder havingthe following composition is prepared:

Ingredient amount/tablet (mg) Core Colesevelam hydrochloride 400Microcrystalline cellulose 150 Hydroxypropyl methyl cellulose 50Colloidal silicon dioxide 10 Magnesium stearate 5 Colon release layerEudragit FS30D 60 PlasACRYL T20, CAS no 123-94-4 6 IBAT inhibitor layerIBAT inhibitor Example 14 7 Hydroxypropylmethyl cellulose 12Croscarmellose sodium 6 Protective coating Hydroxypropylmethyl cellulose12 Polyethylene glycol 2

Colesevelam hydrochloride, microcrystalline cellulose and colloidalsilicon dioxide are mixed and granulated with hydroxypropyl methylcellulose dissolved in water. The granules are dried and mixed withmagnesium stearate and compressed to tablets. The EUDRAGIT FS30Ddispersion and water are stirred into the PIasACRYL T20 and sprayed ontothe core tablets using a suitable coating machine. The IBAT inhibitorcoating suspension is prepared by mixing the IBAT inhibitor,hydroxypropyl methyl cellulose and croscarmellose sodium in water andsprayed onto the tablet cores with the colon release layer using asuitable coating machine. Finally the protective coating solution ofhydroxypropylmethyl cellulose and polyethylene glycol are sprayed ontothe tablets using a suitable coating machine.

Example 20

A Colesevelam colon release tablet having the following composition isprepared:

Ingredient amount/tablet (mg) Core Colesevelam hydrochloride 400Microcrystalline cellulose 150 Hydroxypropyl methyl cellulose 50Colloidal silicon dioxide 10 Magnesium stearate 5 Colon release layerAmylose 30 Eudragit S100 60 Triethylcitrate 6 Glycerolmonostearate 3

Colesevelam hydrochloride, microcrystalline cellulose and colloidalsilicon dioxide are mixed and granulated with hydroxypropyl methylcellulose dissolved in water. The granules are dried and mixed withmagnesium stearate and compressed to tablets. Amylose, Eudragit 100,triethylcitrate and glycerolmonostearate are dissolved in suitablesolvents and sprayed onto the tablet cores using a suitable coatingmachine.

The invention claimed is:
 1. A method for treating cholestasis-inducedpruritus in a subject, the method comprising orally administering to asubject in need of such treatment a therapeutically effective amount anIBAT inhibitor, wherein the IBAT inhibitor is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the subject is diagnosed with a bile acid disease.
 3. The methodof claim 2, wherein the bile acid disease is cholestasis of pregnancy.4. The method of claim 2, wherein the bile acid disease is selected fromthe group consisting of Alagilles syndrome (ALGS), progressive familialintrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), liverfibrosis, non alcoholic fatty liver disease, non-alcoholicsteatohepatitis (NASH), and primary sclerosing cholangitis (PSC).
 5. Themethod of claim 1, wherein treatment of cholestasis-induced pruritusdecreases the level of serum bile acids in the subject.
 6. The method ofclaim 1, wherein treatment of cholestasis-induced pruritus decreases thelevel of liver bile acids in the subject.
 7. The method of claim 1,wherein the subject is a pediatric subject.